Human genetic, epidemiologic, and randomized clinical trial data suggest that therapies that independently lower LDL-C and TRLs reduce the risk of CVD. Inhibiting ANGPTL3 recently emerged as a novel therapeutic approach for reducing both LDL-C and TRLs, which, unlike other lipid-lowering therapies, may protect against diabetes because ANGPTL3-deficient subjects have improved insulin sensitivity. However, the complete metabolic consequences of inhibiting ANGPTL3 in humans and the cellular mechanisms responsible for the cardiometabolic protective effect of ANGPTL3 deficiency remain unknown. In that context, Project 2?s aims will define the role of ANGPTL3 in lipid and glucose metabolism. Aim 1 will determine how ANGPTL3 deficiency alters lipoprotein and glucose metabolism in humans, using in vivo tracer kinetic studies in controls and in a previously recruited family with participants who have either single or biallelic ANGPTL3 loss of function mutations. We will determine how ANGPTL3 deficiency alters fasting and postprandial plasma lipoprotein particle number, size, and composition in addition to adipose tissue and skeletal muscle transcriptional programs related to glucose metabolism. Aim 2 will use subject-specific iPSCs from humans with complete ANGPTL3 deficiency along with corrected isogenic control iPSCs to determine the cellular mechanisms linking ANGPTL3 with lipoprotein (including RLP) and glucose metabolism. Unlike the therapeutic targets of APOB (mipomerson) and MTTP (lomitapide), ANGPTL3 deficiency appears to reduce hepatic VLDL secretion without leading to hepatic steatosis. In addition, unlike other approved LDL-lowering therapies (statins, PSCK9 inhibitors, etc), ANGPTL3 deficiency appears to reduce LDL cholesterol without worsening risk for T2DM. Together, these observations suggest that ANGPTL3 may be working through novel intracellular and extracellular pathways that are yet to be discovered which collectively modulate lipoprotein and glucose metabolism. The studies outlined here are poised to discover these cellular mechanisms which hold the promise to expand our understanding of human biology and identify additional therapeutic targets for the treatment of dyslipidemia while improving glucose levels.